A distinct group of dominantly inherited neurodegenerative disorders is caused by a CAG repeat expansion within the relevant genes, including Huntington’s disease (HD) and various spinocerebellar ataxias (SCA). Recently started RNA-targeting trials aim to reduce the levels of the disease-causing polyglutamine (polyQ) proteins. However, these exciting developments have also raised four new and urgent questions:
- when is the optimal time to start treatment;
- who will benefit from these therapies and can we derive patient-tailored predictions
- can alternative therapeutic strategies be developed to lower the mutant protein that are less invasive, and
- how to aid gene-carriers in personal decisions on life-planning and treatment options?
Patients can be divided in pediatric onset (very long repeats), adult onset (expanded repeats) and intermediate mutation carriers (slightly longer than normal repeats, not always having disease symptoms). Both age-at-onset(AO) and clinical features are very different for these clusters and may require different preventive or therapeutic approaches. While CAG repeat length is predictive, it typically explains about 50% of onset variance. The inter-individual spread in disease onset between people with the same expanded CAG repeat can be decades, implying the existence of additional disease modifiers. Genetic profiling alone has not led to better prediction of disease onset and hence timing and evaluation of preventive interventions. We therefore urgently need robust and sensitive phenotypic, cell biological readouts for proper and patient-tailored prediction of disease onset, disease course and severity. Our consortium composed of academic and biotech researchers, clinicians, ethics experts and patient communities aims to address these questions, and we will define hallmarks that can best be used to predict disease-onset and timing of interventions and to evaluate novel therapeutic strategies. Such is also of utmost importance to clinical and personal decision-making on presymptomatic testing and life planning by at-risk individuals.